PNU-103657
Chemical Name: N-[2-[4-[N-(3-Isobutylpyridin-2-yl)-N-methylamino]piperidin-1-ylcarbonyl]-1H-indol-5-yl]methanesulfonamide
CAS No. 179556-43-5
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Ethyl 5-nitroindole-2-carboxylate (I) was hydrogenated over Pd/C to give amino indole (II),which was condensed with methanesulfonyl chloride,affording sulfonamide (III).Subsequent hydrolysis of the ester group of (III) furnished the intermediate indolecarboxylic acid (IV).
合成路线:Deprotonation of 2-bromopyridine (V) with LDA and subsequent quenching with dimethylformamide provided 2-bromo-3-formylpyridine (VI).Nucleophilic substitution of the bromine of (VI) with N-Boc-4-(methylamino)piperidine (VII) in diisopropylethylamine at 100 C in a sealed tube yielded aminopyridine derivative (VIII).Then,Wittig olefination of (VIII) with the ylide resulting from isopropyl triphenylphosphonium iodide and n-BuLi introduced the isobutenyl substituent giving (IX),and further catalytic hydrogenation furnished the isobutyl derivative (X).The Boc group of (X) was deprotected by treatment with HCl in dioxan to give piperidine (XI).Finally,coupling of (XI) with indolecarboxylic acid (IV) via activation with carbonyl diimidazole yielded the title carboxamide.
📌 参考资料/链接：
参考文献标题:Alkyl substd.piperadinyl and piperazinyl anti-AIDS cpds.
文献作者:Romero,D.L.; Thomas,R.C.; May,P.D.; Poel,T.-J.(Pharmacia Corp.)
参考来源:EP 0797576; JP 1998510530; US 5866589; WO 9618628
📄 详细内容
合成路线:Deprotonation of 2-bromopyridine (V) with LDA and subsequent quenching with dimethylformamide provided 2-bromo-3-formylpyridine (VI).Nucleophilic substitution of the bromine of (VI) with N-Boc-4-(methylamino)piperidine (VII) in diisopropylethylamine at 100 C in a sealed tube yielded aminopyridine derivative (VIII).Then,Wittig olefination of (VIII) with the ylide resulting from isopropyl triphenylphosphonium iodide and n-BuLi introduced the isobutenyl substituent giving (IX),and further catalytic hydrogenation furnished the isobutyl derivative (X).The Boc group of (X) was deprotected by treatment with HCl in dioxan to give piperidine (XI).Finally,coupling of (XI) with indolecarboxylic acid (IV) via activation with carbonyl diimidazole yielded the title carboxamide.
参考文献标题:Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: Effect of 3-alkypyridine ring substitution
文献作者:Genin,M.J.; Poel,T.J.; May,P.D.; Kopta,L.A.; Yagi,Y.; Olmsted,R.A.; Friis,J.M.; Voorman,R.L.; Adams,W.J.; Thomas,R.C.; Romero,D.L.
参考来源:J Med Chem 1999,42(20),4140
产品链接: CAS No. 179556-43-5››